Why we age: chief conductor of the endocrine orchestra
From morning till night all day
Watch believes the sticks shadow.
But if the night the Sun sleeps,
That time, it might be worth?
History of ideas and concepts in gerontology can be summarized as a search for "clock" of aging. At different times these "hours" have been all endocrine glands — gonads, adrenal glands, thyroid gland, pituitary gland.
A famous Russian gerontologist Vladimir M. Dilman believed that the lifetime counts down main conductor of the endocrine orchestra, is situated at the base of the brain, — hypothalamus.
However, in nature there is a natural mechanism that determines all the rhythms of living organisms is the alternation of day and night, light and darkness. The rotation of our planet around its axis and simultaneously around the Sun measures days, seasons and years, with which compare the life expectancy of its inhabitants.
Nature has provided living organisms with a device that is able to perceive light information and convert it into signals that control the body rhythms. The Central part of this device is the upper appendage of the brain, the pineal gland.
Ancient anatomists called it the pineal (pineal) gland for its resemblance to a pine cone. The main function epiphysis's — the transfer of information about the light regime of the environment in the internal environment of the body.
So in the body are supported by physiological rhythms, providing adaptation to environmental conditions. In fish, amphibians, reptiles and birds light passes through a thin skull, and the pineal gland has the ability of direct perception of light signals (perhaps that is why it is called the "third eye").
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Rice. 1. The structural formula of melatonin
In mammals, light information perceived by special cells in the retina Chapters, is transmitted to the pineal gland in the neurons of the suprachiasmatic nucleus (SHA) of the hypothalamus through the barrel of the upper thoracic part of the spinal cord and the sympathetic neurons of the upper cervical ganglion. In the dark signals from SHIA enhance the synthesis and release of noradrenaline from the sympathetic endings.
In turn, this neurotransmitter stimulates the receptors located on the membrane of the pineal cells (pinealocytes), stimulating the synthesis of melatonin (Fig. 1). This is the main pineal hormone — derived biogenic amine, serotonin, formed from the dietary amino acid tryptophan. The activity of enzymes involved in the conversion of serotonin into melatonin is inhibited by light. That is why this hormone is synthesized in the dark, when its blood level is maximum, and in the morning and afternoon hours — minimum (Fig. 2).
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Rice. 2. Biosynthesis and circadian rhythm melatonin
In the body is present and extrarenally (formed out of epiphysis) melatonin. This discovery belongs to Russian researchers N. T. Raichlin and I. M. Kvetnoy: in 1974 they found that in the cells of the vermiform Appendix of the intestine is synthesized melatonin. Then it turned out that this hormone is formed in other parts of the gastrointestinal tract and many other organs — liver, kidney, adrenal gland, gall bladder, ovaries, endometrium, placenta, thymus, and also in leukocytes, platelets and in the endothelium.
Biological effects of melatonin ekstrapiramidnogo implemented directly where it is produced. Synthesis of hormones-hormonal cells confirms the hypothesis of an evolutionary ancient hormone, which, apparently, appeared before the separation of the endocrine glands. The question of whether the path is a synthesis of hormone patentability, still not resolved.
The photoperiod, melatonin and the regulation of daily biological rhythms If the pineal gland to be likened to the biological clock of the body, melatonin can be compared with a pendulum, reducing the amplitude of oscillation of which stops the clock. Perhaps more accurate to liken the pineal gland solar clock, where melatonin plays the role of the shadow from the gnomon — a rod, casting a shadow from the sun. The afternoon sun high and the shadows short (the minimum level of melatonin), in the middle of the night peak of melatonin synthesis by the pineal gland and secrete it into the blood. It is important that melatonin has a circadian (circadian) rhythm, i.e., the unit of measure is the daily rotation of the Earth around its axis.
All biological rhythms are strictly subordinate to the main driver, located in suprachiasmatic nuclei of the hypothalamus. Their molecular mechanism, forming the "hour" genes (Per1, Per2, Per3, Cry-1, Cry-2, Clock, Bmal1/Mop3, Tim, etc.). It is shown that light directly affects the work of those that provide circadian rhythm. These genes regulate the activity of genes key to cell cycle and apoptosis genes. Hormone-a mediator, bringing the guiding signals to the organs and tissues, in fact, serves as melatonin.
The nature of the response is governed not only by its level in blood, but and duration of nocturnal secretion. In addition, melatonin provides the adaptation of endogenous biological rhythms to changing environmental conditions (Fig. 3). The regulatory role of this hormone is universal for all living organisms, as evidenced by his presence and precise rhythm of synthesis in all animals, beginning with unicellular.
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Rice. 3. Synchronization of biorhythms
Due to its amphiphilic properties (soluble in water and fats) melatonin overcomes all the tissue barriers, passes freely through cell membranes. Without a system of receptors and signaling molecules interacting with the nuclear and membrane receptors, it influences intracellular processes. Receptors for melatonin are found in various nuclei of the hypothalamus, retina and other tissues neurogenic and of a different nature.
In healthy children the concentration of melatonin in the blood, gradually increasing up to one year and is maintained at a high level until puberty. At children of younger age night the amount of melatonin higher than the day, about 40 times. In young children this hormone performs two functions: it extends the sleep and suppresses the secretion of sex hormones. In puberty the number of circulating hormone is reduced, and most clearly in the period of puberty. The difference between its daytime and nighttime concentration is reduced to 10 times. Noted that in children with delayed puberty melatonin levels are higher. If the hormone continues to be high (five times or more above age norms), sexual maturation is delayed for a long time.
Probably due to melatonin adults see erotic dreams. Him sleep becomes "fast stage" (paradoxical sleep) and memory come alive in vivid emotional experiences, including those associated with sex. In people aged 60-74 years, most physiological parameters undergo a positive phase shift circadian rhythm of about 1.5–2 hours ahead. In patients older than 75 years there is often a desynchronization in the secretion of many hormones, body temperature, sleep patterns and certain rhythms of behavior that might be related to the pineal gland, whose function during aging is inhibited (Fig. 4).
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Rice. 4. Circadian rhythm in melatonin concentration (PG/ml) in the blood of men of all ages. On the y — axis melatonin, PG/ml; x-axis — time of day, h
If the pineal gland — the sundial of the body, any changes in the duration of daylight should affect its functions and, ultimately, on the rate of aging. In several papers it is shown that the violation of photoperiodicity can significantly reduce life expectancy. American researchers M. Hurd and M. Ralph found that Golden hamsters with a particular mutation in the gene for tau, responsible for the generation of rhythmic signals in suprachiasmatic nucleus of the hypothalamus, lived for 20% less than the control. When in the brain of mutant hamsters implanted cells of the hypothalamus from healthy animals, the normal life span was restored. The destruction suprachiasmatic nuclei leads to a reduction in life expectancy of animals. Dysfunction of some circadian genes causes premature aging and the development of various pathological conditions, including an increase in sensitivity of mice to the development of tumors (table. 1).
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Reproductive function After the invention of electric light at night (often referred to as light pollution) has become an essential part of the modern lifestyle (Fig. 5), leading to serious disorders of behavior and health, including cardiovascular disease and cancer. According to the hypothesis of "circadian destruction", such a change in light regime violates the endogenous circadian rhythms and suppresses nocturnal melatonin secretion and reduces its concentration in blood. Carefully conducted studies have shown that the illumination of 1.3 to 4.0 LK monochromatic blue light or 100 Lux of white light suppresses the production of melatonin by the pineal gland (Fig. 6).
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Rice. 5. View of Earth from space by night
In laboratory rodents, artificially increasing the duration of the light period by 2-4 h prolongs the duration of estrous (ovulation) cycle and in some cases breaking it. Under constant (24 h/day) light exposure, most rats and mice very quickly a condition equivalent to menopause in women. In the ovaries of such animals detect cysts and hyperplasia of cells that produce sex hormones. Instead of the cyclic secretion of gonadotropins, prolactin, estrogens and progesterone characteristic for normal reproductive period, these hormones are formed acyclicity, causing hyperplastic processes in mammary glands and uterus. There is evidence that exposure to light at night reduces the duration of the menstrual cycle in women with long (>33 days) cycle: thus, among the surveyed nurses, often working the night shift, have 60% of it was shorter (25 days), and about 70% complained of his failures. In rats with impaired ovulation, reduced glucose tolerance and insulin sensitivity. It is established that constant illumination increases they have a threshold of sensitivity of the hypothalamus to ugnetajushe action of estrogen. This mechanism is key in the aging of the reproductive system, and in female rats and women. Thus, the influence of light at night leads to anovulation and accelerate the shutdown of reproductive function in rodents and dysmenorrhea in women.
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Fig. 6. Solar spectrum and the sensitivity of retinal cells — cones (color curve) and sticks — to light of different wavelengths
Exposure to constant light enhances lipid peroxidation in animal tissues and reduces total antioxidant and superoxidedismutase activity, whereas the use of melatonin inhibits lipid peroxidation, especially in the brain. Antioxidant effect of melatonin, an outdoor R. Reuter in 1993, confirmed in numerous studies. The main thrust of this operation hormone, protecting nuclear DNA, proteins and lipids, which manifests itself in every cell of a living organism in all cell structures. The antioxidant activity of melatonin is associated with its ability to neutralize free radicals, including those formed during peroxide oxidation of lipids, as well as the activation of glutathione peroxidase a powerful endogenous factor of the enzymatic protection against radical oxidation. In some experiments proved that melatonin neutralizes hydroxyl radicals more actively than the antioxidants glutathione and mannitol, and against peroxyl radicals is two times stronger than vitamin E.
Shift work and health At the present time in some branches of industry the number of people working in shifts quite significantly: for example, in the US, 20%, and in most countries of the European Economic Community, 15-20% of the total. Obvious health problems among replacement workers include sleep disorders, metabolism and tolerance to lipids, gastrointestinal disease, increased incidence of cardiovascular diseases, and possibly diabetes. In this group more often than those working day shifts, there is obesity, high triglycerides and cholesterol, a low concentration of high density lipoprotein. On the other hand, there is evidence that this metabolic syndrome is a risk factor not only of cardiovascular diseases but also of malignant tumors.
There is evidence of a greater number of deaths from malignant neoplasms of replacement workers with experience not less than 10 years compared with working day shifts. In Denmark a large study (about 7 000 surveyed in each group) showed that formal job significantly increases the risk of developing breast cancer in women aged 30 to 54 years. Similar observations are noted in Finland and the USA in the survey of flight attendants on the subject of breast cancer. It was also found that cancer risk increases with more frequent night insomnia, increased levels of night lighting, and when working the night shift. In the latter case, the risk was also increased with increasing experience (table. 2). In Norway in the analysis of health data, almost 45 thousand nurses found that the extra increased risk of breast cancer have worked nights for 30 or more years was 2.21. A similar pattern in relation to colon cancer detected in long-term working at night Seattle residents. The obtained data on the increased risk of colon cancer and rectal cancer in women working in radio and the Telegraph.
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In 2003, E. Schernhammer and her colleagues analyzed the data about state of health 79 thousand nurses found that working the night shift at higher risk of breast cancer. Cancer of the colon and rectum occur more frequently in workers with at least three night shifts a month for 15 years or more. Reported increased risk of prostate cancer in the Scandinavian airlines pilots, depending on the number of long flights. The mechanisms underlying the increased risk of cancer among night workers and flight crews may be associated with impaired circadian rhythms and involuntary exposure to light at night, which leads to decrease production of melatonin, a well-known biological blocker of carcinogenesis.
Light exposure and carcinogenesis In 1964, the German researcher V. Ikle noted that mice under continuous light the number of mammary tumors and the resulting deaths are much larger than animals living in standard mode. A similar pattern was observed in other tumors. In 1966, at the Moscow cancer research center, I. O. Smirnova found hyperplastic processes in mammary gland and mastitis from 78-88% of female rats in 7 months. after the onset of exposure to constant illumination. According to I. A. Vinogradova, when the content of rats under constant lighting up to 18 months of age survives a little more than half the females, while in a room with standard lighting mode by this time was living almost 90% of the animals. A spontaneous tumor was found in 30% of rats kept under constant light vs. 16% in standard mode.
In the experiments conducted in our laboratory, D. A. Baturin, female mice carrying gene for breast cancer HER-2/neu, as a result of constant illumination was observed significantly more cases of adenocarcinoma of the breast in comparison with the standard conditions. The effect was proportional to the light intensity. Exposure to constant light significantly accelerated age-related fertility problems and significantly increased spontaneous carcinogenesis in mice of line CBA. Constant illumination started at the age of 30 days, resulted in accelerated development of spontaneous endometrial adenocarcinomas in rats line BDII/Han.
In 1965, I. K. Haecky from the Kiev Institute of problems of Oncology, first reported on the stimulating effect of constant light on caused by the introduction of 7,12-dimethylbenzanthracene (DMBA) - induced carcinogenesis of mammary glands in rats. When the content of animals from birth at a constant or standard lights a number of cases of adenocarcinoma of mammary glands in rats that received DMBA at the age of 55 days, were, respectively, 95 and 60%. The use of melatonin significantly delayed the development of induced tumours in both groups.
In our experiments, the introduction of rats contained in normal conditions, another carcinogen, N-nitrosodiethylamine (NMM), resulted in 55% animals of adenocarcinomas of the mammary glands. At constant coverage, the number of these tumors was significantly increased, and their latent period decreased. In these rats the serum of increased concentrations of prolactin and melatonin decreased compared to the same indices in rats kept in standard conditions.
In the work of French researchers shows that the violation in rats circadian rhythms, due to the constant light, stimulated carcinogenesis in the liver induced by N-nitrosodiethylamine. A.V. Panchenko also noted that at a constant light in rats increased the number of cases of adenocarcinoma in the ascending and descending parts of the colon with the introduction of 1,2-dimethylhydrazine (DMH) compared to the rats contained in the standard conditions, and also received injections of the carcinogen.
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Together with D. S., Beniashvili studied the effect of constant light on the transplacental carcinogenesis induced by N-nitrosomethylamino. Rats throughout pregnancy and feeding of offspring were kept in a room with the lights switched on around the clock, after which the rats were transferred to normal mode. It turned out that even brief exposure to constant light stimulated the growth of induced tumors of the nervous system and kidneys in the offspring compared with the offspring of rats kept in standard conditions. Thus, constant light activates chemical carcinogens induced tumors of various localizations.
Recently in patients with breast cancer (in 95% of cases) detected changes in the activity of the three clock genes (PER1, PER2, PER3). This may lead to violation of control circadian normal rhythm and thus increase the survival of cancer cells and to enhance neoplastic process. Currently, it is unclear whether unique gene Per2 as a "tumor suppressor" or some other clock genes with similar anti-tumor function. The mechanism of suppression of tumor growth is also unclear, but there is an important observation — cancerous tissue specifically associated with a special time genes. In 2006 came a further six works, indicating the violations of the functions of clock genes in patients with cancer of other localizations.
Data obtained in rats and humans, show that in the tumors, and the individuals vary considerably circadian rhythms. Thus, in our experiments in rats with colon cancer, caused by 1,2-dimethylhydrazine, impaired circadian rhythm of melatonin in the blood serum, the activity of the pinealocytes and the content of biogenic amines in suprachiasmatic nucleus of the hypothalamus and preoptičeskoj area. Thus, environmental and genetic factors that damage the system and/or circadian rhythm, can endanger temporal regulation of cell division and thus enhance the growth of the tumor.
Antistress effects of melatonin The pineal gland is an important anti — stress element "defense" of the body, and melatonin plays an important role as a factor of nonspecific protection. Highly animals and especially human starting point in the development of stress include negative emotions. Melatonin helps to reduce emotional reactivity. To the negative effects of stress can be attributed to the strengthening of free radical oxidation, including lipid peroxidation, damaging cell membranes. Stress is necessarily accompanied by extensive shifts in the endocrine field, which primarily affects the hypothalamic-pituitary-adrenal system. Part of melatonin is the "correction" in nature: the hormone connects to the endocrine regulation only in case of sharp deviations in the adrenal glands.
There is a whole series of evidence of the adverse effects of chronic stress on the immune system. In particular, in individuals a long time is experiencing a stressful situation, reduced the level of T-lymphocytes in the blood. In this situation, melatonin exerts both a direct effect on immune cells and indirectly, via the hypothalamus and other neuroendocrine structures.
Chronic stress (e.g., associated with pain or immobilization) causes misalignment of the circadian rhythm, increase problems with sleep, altered EEG, disturbed secretion of a number of biologically active compounds. Although the main "pacemaker" in the body is not the pineal gland, and suprachiasmatic nucleus of the hypothalamus, both of these education interact with the mediation of melatonin (receptors it has in the cells SHA), which is able to restrict during "rushing hours" primary pacemaker.
Melatonin, aging and tumor development So, in experiments on animals with induced chemical carcinogenesis melatonin inhibits the growth of tumors of different localization (breast, cervix, and vagina, skin, subcutaneous tissue, lung, endometrium, liver, colon), indicating a wide range of its anticarcinogenic action. Data from these animal experiments are in good agreement with the results of clinical observations. So, canadian researchers summarized the results of 10 studies in which melatonin is used to treat cancer patients with solid tumours. From 643 patients treated with melatonin, the relative risk of death decreased to 0,66, and serious side effects of the drug during the year are not registered.
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In recent years, actively discussed the possible mechanisms of the inhibitory effect of melatonin on carcinogenesis and aging. It is established that it is effective at the systemic, tissue, cellular and subcellular levels (table. 3), preventing aging and cancer. At the system level melatonin reduces the production of hormones that contribute to these processes, stimulates immune surveillance, prevents the development of metabolic syndrome. At the same time inhibits the production of oxygen free radicals and activate antioxidant protection. Melatonin inhibits the proliferative activity of the cells and increases the level of apoptosis in the tumors but reduces it in the nervous system, inhibits telomerase activity. At the genetic level, it inhibits the action of mutagens and clastogens, as well as the expression of oncogenes (Fig. 7).
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Rice. 7. Molecular mechanisms of the effect of light and melatonin in aging and cancer
All these data indicate the important role of pineal gland in cancer development. Inhibition of its function under constant light stimulates tumorigenesis. Epidemiological observations on increased risk of breast cancer and colon cancer in night shift workers correspond to the results of experiments on rodents. The application of the epiphyseal hormone inhibits carcinogenesis in animals and in normal lighting mode and constant lighting. So, melatonin may be highly effective for cancer prevention, especially in the Northern regions where the summer is always a light ("white nights"), and during the long polar night everywhere is lit electric light.
Unlike many hormones, the effect of melatonin on cellular structure depends not only on its concentration in the blood and the extracellular environment, but also on the initial state of the cell. This suggests that endogenous melatonin is a versatile adaptogen that supports balance in the body at a certain level, and promote adaptation to continuously changing environmental conditions and local influences on the body.
Currently, in many countries available melatonin preparations that are registered as medicines or as dietary supplements. Today there is some experience of their use in the treatment of various diseases, above all for sleep disorders, gastric ulcer and duodenal ulcer, hypertension.
Many studies have shown that melatonin slows the aging process and increases the lifespan of laboratory animals — fruit flies, flat worms, mice, rats. Optimism cause the publication of its ability to increase resistance to oxidative stress and to alleviate symptoms of certain age-associated diseases, such as macular degeneration of the retina, Parkinson's disease, Alzheimer's disease, hypertension, diabetes. Comprehensive clinical testing of this hormone will greatly expand its application for the treatment and prevention of age-related diseases and, ultimately, premature aging. published
Author: V. N. Anisimov, doctor of medical Sciences
See also: the Power of mother's curse or the new discoveries of epigenetics